tbuckley/cabot-search huggingface dataset:
TMIC-75. SPATIALLY-RESOLVED TRANSCRIPTOME ANALYSIS OF BRAIN METASTATIC BREAST CANCER REVEAL KEY MEDIATORS OF BRAIN-TROPIC METASTATIC POTENTIAL
Authors: Maxine Umeh-Garcia, Bryanna Godfrey, Pablo Nunez Perez, Sushama Varma, Saman Ahmadian, Angus Toland, Monica Granucci, Inna Averbukh, Lu Tian, Robert West, Michael Angelo, Sylvia Plevritis, Melanie Hayden Gephart
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In women with metastatic breast cancer, 30% (HER2+) to 50% (triple negative) develop brain metastases. Breast-to-brain metastasis carries a poor median survival of only 10 months and is accompanied by severe neurologic decline. Halting the progression of breast cancer brain metastases requires modulation of the tumor microenvironment (TME), yet little is known about how the primary breast TME affects brain tropism, or how, once there, metastatic cancer cells interact with normal brain cells (e.g., neurons, astrocytes, microglia). METHODS We constructed a large (n = 253 cores), diverse, clinically-annotated tissue microarray (TMA) of breast cancer brain metastases with surrounding brain (n = 127), associated primary breast tumors (n = 67, with 30 matched), normal brain (n = 23), and staining control (n = 18) tissue samples, from patients (n = 140) treated at Stanford Hospital between 2008 – 2018. We then leveraged a combination of genome-wide transcriptome analysis and high resolution spatial imaging (using GeoMx Digital Spatial Profiling) to interrogate the distinct, spatially-driven gene signatures of tumor, immune, and normal brain cells within the breast cancer brain metastasis TME. RESULTS We revealed novel gene regulatory programs that are associated with metastatic potential from the primary breast to the brain. We also identified not only diverging features of the breast and brain TMEs, but equivalent features which may contribute to preferential honing and outgrowth of metastatic breast cells in the brain microniche. Additionally, we uncovered significant cellular crosstalk between tumor, immune, and brain cell populations, including putative cell-cell interactions and intercellular signaling pathways. CONCLUSION These results served as a starting point for identifying key tumor-immune-brain interactions responsible for priming immune and brain tolerance of malignant cells, allowing outgrowth and progression of breast cancer brain metastases. Further investigation focused on tumor-brain crosstalk, specifically tumor-microglia interactions, will provide promising targets for therapeutic advancements.
TMIC-68. SIRPΑ BLOCKADE AS AN IMMUNOTHERAPEUTIC STRATEGY TO TREAT BREAST CANCER BRAIN METASTASIS
Authors: Yu-Ting Tsai, Adam Wilson, Katherine Cook, Dawen Zhao, Glenn Lesser, David R Soto-Pantoja
Journal: Neuro-Oncology (2023)

Abstract Triple-negative breast cancer (TNBC) has a high incidence of brain metastasis, with no standard therapeutic strategy for treatment. Therefore, new targets are urgently needed to overcome disease mortality. The CD47/SIRPα signaling pathway is implicated in tumor progression due to bypassing innate and adaptive immune surveillance. Most strategies targeting this pathway focus on targeting the receptor CD47; however, direct targeting SIRPα as a potential approach to mitigate metastatic burden remains understudied. Single-cell-RNA-sequencing indicates that SIRPα expression on basal epithelial cells, and TCGA data shows SIRPα expression is associated with a significant reduction in survival in basal-like breast cancer. Our immune staining against SIRPα in breast cancer patient biopsies shows a 3.5-fold increase in expression in metastatic lesions compared to the primary tumor (n=19; p ≤ 0.01). Staining of 4T1 parental and brain-trophic 4T1-Br3 cells showed an 84% increase in SIRPα in the metastatic cells (n=3; p ≤ 0.05). Furthermore, Real-time cell impedance analysis revealed that SIRPα blockade inhibits TNBC 4T1br3 cell migration (n=4; p≤0.01), suggesting a link between SIRPα expression and metastatic potential. Furthermore, in vivo SIRPα blockade reduced brain metastatic burden by approximately 90%, (n=4-7; p ≤ 0.05). Digital spatial profiling of tissues revealed that SIRPα blockade was associated with reductions in immune checkpoints, including CTLA-4, PD-1, PD-L1, and LAG3, and immunosuppressive T-cell/monocyte populations. Furthermore, our spatial analysis indicated that brain lesions of WT mice have increases in the extracellular matrix protein fibronectin in the immune enriched regions, potentially serving as a barrier for immune cell infiltration contributing to invasion, metastasis, and immune evasion, was reduced by 70% in SIRPα treated brain lesions (n-3-6; p ≤ 0.05). Thus, these data suggest that SIRPα blockade may influence the tumor microenvironment to limit brain metastatic breast cancer growth and potentially enhance patient survival to metastatic brain disease.
QOL-09. QUALITY OF LIFE AFTER SURGERY FOR LOWER GRADE GLIOMAS
Authors: Anne Heffernan, Yilun Wu, Luke Benz, Roel Verhaak, Bethany Kwan, Elizabeth Claus
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Limited data exist on long-term quality of life (QOL) for adults diagnosed with lower grade glioma (LGG). METHODS QOL was assessed for 320 adults with LGG (World Health Organization grade 2/3) enrolled in the International Low Grade Glioma Registry using the Medical Outcomes Study 36-Item Short Form (SF-36) health survey. Data on symptoms were also collected. QOL outcomes were examined by treatment group and also compared to those from a population-based case/control study of meningioma (the Meningioma Consortium), in which 1722 meningioma cases diagnosed among residents of Connecticut, Massachusetts, California, Texas, and North Carolina from May 1, 2006 through March 14, 2013 were enrolled and frequency matched to 1622 controls by age, sex and geography. RESULTS The LGG sample average age is 45 years at time of interview and 53.1% male. Almost 55% of patients had received radiation and chemotherapy (primarily temozolomide); 32.4% had received neither treatment. Almost 2/3 LGG subjects report difficulty with speaking, memory, or thinking and over 1/3 report personality change or difficulty driving. After controlling for age and other co-morbidities, individuals diagnosed with LGG report levels of physical, emotional, and mental health functioning below those reported in a meningioma as well as a general healthy population. CONCLUSIONS Despite being relatively young, persons with LGG report significantly reduced QOL compared to persons with non-malignant brain tumors and to a control population, highlighting the need to better acknowledge and manage these symptoms for this group of patients diagnosed in the prime of life.
EPID-13. DATA-DRIVEN MACHINE LEARNING MODELS AS PROGNOSTIC TOOL FOR PREDICTING SURVIVAL OUTCOMES IN PEDIATRIC PATIENTS WITH GLIOMA OF THE OPTIC APPARATUS
Authors: Nolan Brown, Cathleen Kuo, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract Optic pathway gliomas (OPG) are low-grade lesions arising from the astrocytes of the visual pathway and diencephalon. For most patients, observation appears to be the treatment of choice, but it remains unclear how frequently serial imaging should be obtained and at what point lesions can be deemed to have become quiescent. There is therefore an ongoing need for prognostication tools that can accurately predict the behavior of OPG to help identify those lesions meriting therapeutic intervention. In the present study, we leverage population-level data from the Surveillance, Epidemiology, and End. RESULTS: program (SEER) database to develop a predictive calculator for overall survival (OS) in pediatric OPG. Accordingly, we extracted all available patient-level data from the SEER database. Training and testing datasets were established. Cox proportional hazards regressions were then used to identify independent predictors of survival, and model validation was performed. A total of 1,052 pediatric patients met inclusion criteria. Most were between 5 to 9 years old (45.7%), males (51.6%), white (85.6%), non-Hispanic (82.1%), and 232 patients (22.1%) came from houses with a median income less than $54,999, while 111 patients (10.6%) lived in a rural county. Nearly 90% of patients did not undergo surgical debulking. Twenty-three patients (2.2%) received radiotherapy and 294 (27.9%) received chemotherapy. Additionally, univariate and multivariate analyses were performed to identify variables associated with OS. Median household income and subtotal resection were found to be predictors of OS on univariate analysis. Furthermore, on multivariate analysis, median household income greater than $55,000 and subtotal resection were predictive of higher OS. Age at diagnosis, sex, rural versus urban setting, benign versus malignant behavior, and use of chemotherapy or radiotherapy did not appear to affect OS. Finally, we created a calculator (https://spine.shinyapps.io/optic_glioma/) using our model to estimate 5-,10-, and 1-year OS probability and other survival outcomes.
PATH-67. SHH/GLI3 SIGNALOPATHIES AND NEURO-ONCO-GENETIC COUNSELING : A TUNISIAN PEDIGREE
Authors: Nouha Bouayed Abdelmoula, Balkiss Abdelmoula
Journal: Neuro-Oncology (2023)

Abstract Here, we present a 3-generation pedigree of a Tunisian non-consanguineous family with six offspring affected by heterogeneous forms of the GLI3-related PHS spectrum. Our aim was to assess the neuro-onco-genetic risks and provide counseling for appropriate clinical follow-up. A non-consanguineous couple was referred to our genetic counseling due to the termination of their first pregnancy, which was diagnosed with multiple congenital anomalies. An autopsy examination, including pathological and radiographic analysis, was conducted. Furthermore, a medical genetic assessment considering a family history spanning over three generations as well as cytogenetic analysis were carried out. The index case was diagnosed with GLI3-related PHS based on facial dysmorphic features, auricular malformations, and unilateral postaxial toe syndactyly, along with brain macro-calcifications. The index case's father and his brother exhibited facial dysmorphic features. Furthermore, two cousins from one of their paternal uncles presented another form, associated respectively with unilateral renal agenesis and unilateral hand agenesis. The remaining three cases, who belong to the first generation, and passed away during infancy, exhibited the same condition, associated to congenital heart defect in one of them. The heterogeneity of GLI3-related overlapping conditions (SHH/GLI3 signalopathies) result from the location of GLI3 mutations in different domains of the gene, as well as the resulting functional balance between activating and repressive forms of GLI3 during development. The report of a late diagnosis of GLI3-related PHS following the discovery of hypothalamic hamartomas as well as the description of a new nonsense germline mutation in a child with Greig syndrome and medulloblastoma, support that neuro-oncological investigation of GLI3 families could be beneficial.
CTNI-59. RARE AND NOVEL <i>KIAA1549-BRAF</i> FUSION BREAKPOINTS PREDICT POOR CLINICAL OUTCOME FOR PATIENTS WITH RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA: PHASE II PNOC001 TRIAL RESULTS
Authors: Sebastian Waszak, Mariam Aboian, Jane Minturn, Sarah Leary, Mohamed S Abdelbaki, Stewart Goldman, Jennifer Elster, Adam Kraya, Matthew Lueder, Divya Ramakrishnan, Marc von Reppert, Kevin Liu, Adam Resnick, David Solomon, Annette Molinaro, Joanna Phillips, Michael Prados, Daphne Haas-Kogan, Sabine Mueller
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVES PNOC001 sought to estimate progression-free survival (PFS) associated with everolimus for progressive/recurrent pediatric low-grade glioma (pLGG) and to determine if activated PI3K/AKT/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) was associated with response. A secondary objective was to assess whether somatic drivers influence median PFS. METHODS Patients, 3-21 years of age, with recurrent/progressive pLGG received everolimus orally at 5 mg/m2 daily. Somatic drivers, when available, were associated with PFS and compared to four independent molecular pLGG cohorts with newly-diagnosed and progressive/recurrent patients. RESULTS From 2012 to 2019, 65 subjects enrolled [median age 9.6 years, 3.0-19.9; 46% female]; Median PFS for all-comers was 11.1 months (95%-CI 7.6-19.8, n = 64). PFS was not modulated by PI3K/AKT/mTOR pathway activation (median PFS 11.2 vs 9.4 months, P = 0.83, n = 62). BRAF alterations were identified in 67.8% (40/59) of patients. Rare/novel KIAA1549-BRAF fusion breakpoints were enriched in PNOC001 compared to newly-diagnosed pLGGs in independent cohorts (28.6% vs 2.6%, P = 1.4e-4, n = 214). In PNOC001, patients with rare/novel KIAA1549-BRAF fusion breakpoints had worse clinical outcomes than patients with common fusion breakpoints (median PFS 6.1 vs 16.7 months, P &amp;lt; 0.05, n = 20). Rare/novel KIAA1549-BRAF fusion breakpoints were also enriched in patients with progressive/recurrent disease in independent pLGG cohorts (17.6% vs 2.6%, P = 2e-3, n = 227). Integration of BRAF alterations and DNA methylation-based tumor subtypes further revealed that rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline (14.1%) compared to infratentorial (2.0%) pilocytic astrocytomas (P = 1e-4). KIAA1549-BRAF fusion breakpoints remained risk factors for progressive/recurrent disease in PNOC001 (P = 0.05) and independent pLGG cohorts (P &amp;lt; 0.05) after accounting for tumor location and DNA methylation subtypes. CONCLUSIONS Rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline pLGGs and define independent genomic risk factors for disease progression/recurrence. Our results indicate that future clinical trials must interrogate and define KIAA1549-BRAF fusion breakpoints for informative results and conclusions.
CTNI-85. GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB
Authors: Patrick Wen, Brian Alexander, Donald Berry, Meredith Buxton, Webster Cavenee, Howard Colman, John de Groot, Benjamin Ellingson, Gary Gordon, Emma Hyddmark, Mustafa Khasraw, Michael Lim, Ingo Mellinghoff, Tom Mikkelsen, James Perry, Ashley Powell, Erik Sulman, Kirk Tanner, Michael Weller, W K Alfred Yung, Nicolas Blondin, Andrew Brenner, Omar Butt, Macarena de la Fuente, Jan Drappatz, Fabio Iwamoto, Lyndon Kim, Eudocia Lee, Megan Mantica, Burt Nabors, Herbert Newton, David Schiff, Tobias Walbert, Shiao-Pei Weathers, Timothy Cloughesy, Andrew Lassman
Journal: Neuro-Oncology (2023)

Abstract GBM AGILE (NCT03970447;https://www.gcaresearch.org/research/gbm-agile) is a phase 3 Bayesian adaptive platform trial that efficiently tests multiple arms against common control, with 6 arms included to date. Primary endpoint is overall survival (OS). Stage 1 experimental arms are adaptively randomized against other arms. Demonstrated efficacy in stage 1 leads to fixed randomization stage 2. Stages 1 and 2 are combined for registration. Control randomization is fixed. Regorafenib, a multikinase-inhibitor, entered into GBM AGILE as the first arm and therefore was equally randomized against control. Regorafenib showed OS benefit in recurrent disease (RD) in randomized phase 2 REGOMA trial. METHODS: Patient subtypes in GBM AGILE are newly diagnosed unmethylated (NDU), RD, and—not considered for regorafenib—ND methylated (NDM). Arm indications (signatures) are combinations of subtypes. Control is temozolomide (ND) and lomustine (RD). Efficacy is assessed by OS hazard ratio(HR), arm/control. Efficacy is demonstrated when Bayesian probability of benefit (HR&amp;lt; 1.00) ≥ 98% (roughly analogous P-value: 0.02). Futility occurs at any monthly analysis when Bayesian predictive power (PP) is &amp;lt; 25% for all signatures. Follow-up continues for 12 months after arm’s accrual stops. RESULTS: for regorafenib: When PP for all 3 pre-defined signatures was &amp;lt; 25%, regorafenib’s accrual was stopped for futility. Regorafenib/control sample sizes were 49/51, 126/128, 175/179 for signatures NDU, RD, and both. Respective PPs: 0.138, 0.030, 0.025—none close to 0.25. Respective mean HRs: 1.26, 1.25, 1.23. Probabilities of benefit (HR&amp;lt; 1.00): 0.35, 0.18, 0.17. At final analysis, mean HRs were 1.07, 1.12, 1.10 with final probabilities of benefit (HR&amp;lt; 1.00) equal to 0.43, 0.24, 0.24—none close to 0.98. CONCLUSION: GBM AGILE efficiently and compellingly addressed regorafenib’s role in GBM, in RD and NDU. These findings are germane as they fail to confirm the REGOMA results in RD. GBM AGILE continues to efficiently assess other therapies, including utilizing concurrent and previously accrued controls.
ANGI-05. CDKN2A/B HOMOZYGOUS DELETION IN IDH-MUTANT ASTROCYTOMA ALTERS TUMOR CELL INVASION AND VASCULAR FORMATION
Authors: Dustin Grief, Fulvio D'Angelo, Francesca Caruso, Christopher Sereduk, Michele Ceccarelli, Leland Hu, Joseph Loftus, Nhan Tran, Shannon Fortin Ensign
Journal: Neuro-Oncology (2023)

Abstract High-grade gliomas represent the most common type of primary adult malignant brain tumor historically diagnosed and graded from histologic criteria alone. Gliomas harboring isocitrate dehydrogenase (IDH) 1 or 2 mutations are associated with lower grade tumors and portend a favorable prognosis relative to IDH-wildtype glioma. However, molecular profiling has identified additional alterations in lower grade gliomas that confer an aggressive high-grade phenotype and a worse clinical prognosis. Of these, the loss of CDKN2A/B in IDH-mutant astrocytoma is the strongest implicated alteration and is sufficient to define a grade 4 tumor regardless of histologic grade. However, there remain no effective therapies targeted at molecular subgroups in aggressive gliomas to date. Here, we sought to elucidate the biologic pathways and functional outcomes associated with the acquisition of high-grade behavior under loss of CDKN2A/B in IDH-mutant astrocytoma to inform future therapeutic strategies. We analyzed a cohort of patient IDH-mutant astrocytomas with whole exome and RNA sequencing data and found several candidate genes/pathways regulated concurrent with CDKN2A/B loss, including regulators of embryonic development, extracellular matrix organization and regulation of vascular processes. Moreover, we identified 1 tumor that displayed intratumoral heterogeneity of CDKN2A/B expression across biopsies. Using grade 4 IDH-mutant astrocytoma patient-derived (PDX) and established cell-lines harboring CDKN2A/B homozygous deletion, we then stably re-expressed cell cycle regulators p14, p15, and p16 using a Tet-inducible lentiviral system and confirmed their decreased proliferation as compared to parental lines. IDH-mutant cell lines with re-expression of p14, p15 or p16 were characterized by differential transcription factor activation and distinct vascular formation patterns as compared to parental lines. These lines also displayed an increased cell migration and invasive potential and were associated with enhanced integrin signaling through integrin beta-3. Together, our work supports a hypothesis of regional tumor evolution with distinct biologic phenotypes across IDH-mutant gliomas.
QOL-27. EXPLORING DYADIC CHANGES IN ANXIETY AND DEPRESSION SYMPTOMS FOR PRIMARY BRAIN TUMOR PATIENTS AND THEIR FAMILY CAREGIVERS
Authors: Kelsey Bacharz, Anjelica Body, Alayna Ernster, Grace Ann Hanvey, Maryam Rahman, Duane Mitchell, Adaixa Wilborn, Deidre Pereira, Ashley Ghiaseddin
Journal: Neuro-Oncology (2023)

Abstract A primary brain tumor (PBT) diagnosis impacts not only the diagnosed person but their family caregivers. Prior research has established that the psychosocial outcomes (i.e., fear of cancer recurrence, quality of life) of individuals with a PBT and their caregivers are interrelated. Actor-partner interdependence modeling (APIM) can account for this interdependence and be used to assess for dyadic changes over time or different variables. The purpose of the present study was to assess longitudinal dyadic changes in anxiety and depressive symptoms for PBT patients and their caregivers. 38 PBT patient/caregiver dyads completed assessments of anxiety and depressive symptoms during routine oncology clinic visits. All dyads completed at least two assessments, at least 8-weeks apart utilizing the PROMIS anxiety and depression short forms. APIM analyses via mixed linear modeling revealed significant actor effects for both depression and anxiety symptoms (i.e., how the same person’s scores are related from baseline to follow-up) but non-significant partner effects (i.e., how one person’s score at the first timepoint is related to the other person’s score at the second timepoint). Specifically, a one-point increase in T-score at the first timepoint was associated with the same person having a 0.58 increase in their PROMIS depression T-score and 0.50 increase in their PROMIS anxiety T-score, respectively, at the second timepoint (p &amp;lt; .001). There were no significant partner effects detected for depression (p = .168) or anxiety (p = .998). Despite the lack of significant relationship between patient and caregiver outcomes in these results (possibly influenced by small sample size), it is notable that, overall, there was an increase in psychological distress over time for both depression and anxiety symptoms for both patients and caregivers. Thus, future research should continue to focus on how to reduce distress and ensure that both patients and caregivers are supported throughout the disease trajectory.
IMMU-28. TREM2 INHIBITION REPROGRAMS MYELOID CELLS TO STIMULATE ANTI-TUMOR IMMUNITY THROUGH BOTH DIRECT AND INDIRECT MECHANISMS
Authors: Rui Sun, Rowland Han, Colin McCornack, G Travis Tabor, Jinchao Hou, Ryan Cleary, Diane Mao, Qin Liu, Kathleen Schoch, Jingqin Luo, Allegra Petti, Timothy Miller, Jason Ulrich, David Holtzman, Albert Kim
Journal: Neuro-Oncology (2023)

Abstract The prevailing view is that myeloid cells—macrophages and microglia—in the tumor microenvironment (TME) are immunosuppressive and promote glioblastoma (GBM) progression. However, myeloid cells have the functional plasticity to restrict or support tumor cell growth. TREM2 plays important roles in brain microglial function in neurodegenerative diseases, but the functional role of TREM2 in the GBM TME and whether TREM2 represents a meaningful therapeutic target remain largely unknown. To address these questions, we investigated the immune and tumor cell consequences of TREM2 inhibition by multiple orthogonal approaches—transgenic mice, antisense oligonucleotides, and blocking antibodies—in immunocompetent preclinical models (SB28, NPA C54B) and human GBM samples through bulk and single cell RNA-sequencing, flow cytometry, biochemistry, and functional assays. We found TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors, and that high TREM2 expression correlates with poor prognosis in GBM patients. TREM2 loss of function in human macrophages and mouse myeloid cells increased IFNγ-induced immunoactivation and proinflammatory polarization. Conditioned media from TREM2 deficient human macrophages directly killed patient-derived GBM tumor cells, and biochemical analysis identified TNF and other putative tumoricidal proteins in this conditioned media. In mouse GBM models, mice with chronic and acute Trem2 loss of function demonstrated increased tumor cell death and increased animal survival. Trem2 inhibition reprogrammed myeloid cell phenotypes and increased PD-1+CD8+ T cells in the TME. Remarkably, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment in vivo. Trem2 inhibition suppresses tumor cell growth through direct and indirect immune cell mechanisms--by reshaping myeloid subset and T cell functions. Thus, Trem2 inhibitory strategies, in combination with immune checkpoint blockade, may represent an attractive new approach for GBM therapy.